EP0491330A1 - Procédé pour la préparation de l'acide diméthylcyclopropanecarboxylique - Google Patents

Procédé pour la préparation de l'acide diméthylcyclopropanecarboxylique Download PDF

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Publication number
EP0491330A1
EP0491330A1 EP91121549A EP91121549A EP0491330A1 EP 0491330 A1 EP0491330 A1 EP 0491330A1 EP 91121549 A EP91121549 A EP 91121549A EP 91121549 A EP91121549 A EP 91121549A EP 0491330 A1 EP0491330 A1 EP 0491330A1
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EP
European Patent Office
Prior art keywords
ester
acid
base
preparation
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP91121549A
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German (de)
English (en)
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EP0491330B1 (fr
Inventor
Thomas Dr. Meul
Ulrich Dr. Kämpfen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lonza AG
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Lonza AG
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Publication of EP0491330A1 publication Critical patent/EP0491330A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Definitions

  • the invention relates to a new process for the preparation of R, S-2,2-dimethylcyclopropanecarboxylic acid, which is abbreviated below as R, S-2,2-DMCPCS.
  • R, S-2,2-DMCPCS is an important intermediate for the production of S - (+) - 2,2-dimethylcyclopropanecarboxamide (hereinafter abbreviated as S - (+) - 2,2-DMCPCA), R, S-2 , 2, DMCPCS is converted into the optically pure S - (+) - enantiomer by racemate resolution and is subsequently converted into the S - (+) - 2,2-DMCPCA via acid chloride (Lit .: EP 093 511).
  • S - (+) - 2,2-DMCPCA in turn serves as the starting material for the production of the dehydropeptidase inhibitor cilastatin, which is administered in therapy together with penem or carbapenem antibiotics in order to deactivate the antibiotics by a renal dehydropeptidase in the To prevent kidney (Lit .: EP 048 301).
  • a major disadvantage of this process is that large amounts of potassium tosylate are obtained as waste products for disposal and moderate yields (28%) are achieved.
  • a major disadvantage of this process is that the 2,2-dimethylcyclopropanecarboxylic acid ester is obtained in very poor yield (9%) and the overall yield of the corresponding acid is therefore even lower.
  • Another disadvantage of this process is the use of the expensive sulfur ylide derivative.
  • R, S-2,2-DMCPCS Another process for the production of R, S-2,2-DMCPCS is described in DE-PS 27 51 133.
  • the 4-chloro-4,4-dimethylbutyric acid ester is first prepared from a lactone derivative and this is cyclized in the presence of alcoholates to give the R, S-2,2-dimethylcyclopropanoic acid ester, which is subsequently hydrolyzed.
  • a major disadvantage of this process is that the lactone is not commercially available and has to be prepared in a multi-stage synthesis.
  • the object of the invention was to eliminate these disadvantages and to provide a simple and economical process for the preparation of R, S-2,2-dimethylcyclopropanecarboxylic acid, the R, S-2,2-DMCPCS being obtained in good yields.
  • the process is carried out in such a way that isobutylene oxide of the formula with a phosphonoacetic acid trialkyl ester of the formula wherein R1, R2 and R3 are the same or different and are a C1-C4 alkyl group, branched or unbranched, in the presence of a base in an R, S-2,2-dimethylcyclopropanecarboxylic acid C1-C4 alkyl ester of the general formula wherein R3 has the meaning given, converted, and hydrolyzed the ester to the end product in the presence of a base.
  • the phosphonoacetic acid trialkyl esters can be obtained by reacting a trialkoxyphosphine with a halogenoacetic acid ester (Houben-Weyl, Methods of Organic Chemistry, 4th Edition, Volume: Phosphorus Compounds I, pp. 173-176).
  • phosphonoacetic acid trialkyl ester is phosphonoacetic acid triethyl ester or diethylphosphonoacetic acid isopropyl ester.
  • Phosphonoacetic acid triethyl ester is preferably used.
  • the reaction of the phosphonoacetic acid trialkyl ester with isobutylene oxide is carried out in the presence of a base.
  • a base An alkali metal hydride such as sodium hydride, potassium hydride or lithium hydride can be used as the base, for example.
  • the base is expediently used in equimolar amounts to the phosphonoacetic acid trialkyl ester.
  • the reaction temperature is advantageously between 100 and 140 ° C, preferably between 110 and 130 ° C.
  • High-boiling aromatic hydrocarbons or polar solvents can be used as solvents.
  • xylene or xylene isomer mixtures can be used as high-boiling aromatic hydrocarbons.
  • Glycol ethers, such as diethylene glycol dimethyl ether, for example, can be used as the polar solvent.
  • a high-boiling aromatic hydrocarbon, such as, for example, o-xylene, is preferably used as the solvent.
  • R, S-2,2-dimethylcyclopropanecarboxylic acid C1-C4 alkyl ester is then conveniently hydrolyzed without isolation, in the presence of a base to the desired R, S-2,2-DMCPCS.
  • An alkali metal hydroxide is expediently used as the base for the ester hydrolysis.
  • Sodium hydroxide or potassium hydroxide for example, can be used as the alkali hydroxide.
  • ester hydrolysis is expediently carried out with 1 to 2 mol of base, preferably with 1.2 to 1.5 mol, based on 1 mol of R, S-2,2-dimethylcyclopropanecarboxylic acid ester.
  • the ester hydrolysis is expediently carried out at a temperature of from 40 ° C. to the reflux temperature of the solvent used, preferably at the reflux temperature.
  • the ester hydrolysis is expediently carried out in a mixture of one of the high-boiling aromatic hydrocarbons mentioned with an aqueous alcoholic solution.
  • Lower alcohols such as, for example, methanol or ethanol, can be used as alcohols.
  • the R, S-2,2-dimethylcyclopropane carboxylic acid can be isolated after a reaction time of 2 to 3 hours, for example by acidifying the reaction mixture and subsequent extraction.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP91121549A 1990-12-17 1991-12-16 Procédé pour la préparation de l'acide diméthylcyclopropanecarboxylique Expired - Lifetime EP0491330B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH3991/90 1990-12-17
CH399190 1990-12-17

Publications (2)

Publication Number Publication Date
EP0491330A1 true EP0491330A1 (fr) 1992-06-24
EP0491330B1 EP0491330B1 (fr) 1995-03-22

Family

ID=4267768

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91121549A Expired - Lifetime EP0491330B1 (fr) 1990-12-17 1991-12-16 Procédé pour la préparation de l'acide diméthylcyclopropanecarboxylique

Country Status (9)

Country Link
US (1) US5149869A (fr)
EP (1) EP0491330B1 (fr)
JP (1) JPH04266844A (fr)
AT (1) ATE120178T1 (fr)
CA (1) CA2056840A1 (fr)
DE (1) DE59105000D1 (fr)
DK (1) DK0491330T3 (fr)
ES (1) ES2069809T3 (fr)
NO (1) NO175588C (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2124714T3 (es) * 1991-07-26 1999-02-16 Lonza Ag Procedimiento de ingenieria genetica para la preparacion de s-(+)-2,2-dimetilciclopropanocarboxamida mediante microorganismos.
NZ529625A (en) * 2001-05-18 2006-02-24 Ranbaxy Lab Ltd Process for the preparation of amorphous cilastatin sodium
GB0615620D0 (en) * 2006-08-05 2006-09-13 Astrazeneca Ab A process for the preparation of optically active intermediates

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2751133A1 (de) * 1977-11-16 1979-05-17 Degussa Verfahren zum cyclisieren von gamma-chlorcarbonsaeureestern
EP0048301A1 (fr) * 1980-09-24 1982-03-31 Merck & Co. Inc. 2-(Cyclopropancarboxamido)-2-alcèneacides, leurs esters et sels, et compositions bactériostatiques à base de ces composés avec un composé du type thiénamycine
US4542235A (en) * 1982-04-12 1985-09-17 Sumitomo Chemical Company, Limited Method for producing an optically active 2,2-dimethylcyclopropanecarboxylic acid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Band 68, Nr. 5, 29 Januar 1968, Columbus, Ohio, USA, S. R. LANDOR et al., "Cyclopropanes from alpha, beta-unsaturated esters by the dimithylsulfoxonium methylide reaction", Seite 2058, abstract-nr. 21 563e; & J. Chem. Soc., C 1967, vol. 23, pages 2495-2500 (Eng). *
PATENT ABSTRACTS OF JAPAN, unexamined applications, E Field, Band 7, Nr. 285, 20 Dezember 1983, THE PATENT OFFICE JAPANESE GOVERNMENT, Seite 164 C 201; & JP-A-58 164 542 (SUMITOMO). *

Also Published As

Publication number Publication date
US5149869A (en) 1992-09-22
CA2056840A1 (fr) 1992-06-18
ATE120178T1 (de) 1995-04-15
DE59105000D1 (de) 1995-04-27
EP0491330B1 (fr) 1995-03-22
NO914965D0 (no) 1991-12-16
JPH04266844A (ja) 1992-09-22
NO175588B (no) 1994-07-25
ES2069809T3 (es) 1995-05-16
NO175588C (no) 1994-11-02
DK0491330T3 (da) 1995-04-18
NO914965L (no) 1992-06-18

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